Bromodomain and Extra-Terminal Inhibitor BMS-986158 Reverses Latent HIV-1 Infection In Vitro and Ex Vivo by Increasing CDK9 Phosphorylation and Recruitment

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 15; no. 3; p. 338
• Main Authors: Huang, Xu-Sheng, Tian, Ren-Rong, Ma, Meng-Di, Luo, Rong-Hua, Yang, Liu-Meng, Peng, Guang-Hui, Zhang, Mi, Dong, Xing-Qi, Zheng, Yong-Tang
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.03.2022; MDPI
• Subjects: BET; BMS-986158; Cell cycle; Clinical trials; Cyclin-dependent kinases; Cytotoxicity; Drug dosages; Gene expression; HIV; HIV-1; Human immunodeficiency virus; Immune system; Infections; Kinases; latency reversing agent; latent reservoir; Lymphocytes; Phosphorylation; Proteins; RNA polymerase; BET; HIV-1; BMS-986158; latency reversing agent; latent reservoir
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph15030338

Latent reservoir persistence remains a major obstacle for curing human immunodeficiency virus type 1 (HIV-1) infection. Thus, strategies for the elimination of latent HIV-1 are urgently needed. As a bromodomain and extra-terminal (BET) inhibitor, BMS-986158 has been used in clinical trials for advanced solid tumors and hematological malignancies. Here, we found that BMS-986158 reactivated latent HIV-1 in three types of HIV-1 latency cells in vitro, and in combination antiretroviral therapy (cART)-treated patient-derived peripheral blood mononuclear cells ex vivo, without influencing global immune cell activation. BMS-986158 reactivated latent HIV-1 by increasing phosphorylation of CDK9 at Thr186 and promoting recruitment of CDK9 and RNA polymerase II to the HIV-1 long terminal repeat in J-Lat cells. Furthermore, BMS-986158 exerted strong synergism in reactivating latent HIV-1 when combined with prostratin and vorinostat and enhanced the antiviral activity of anti-HIV-1 drugs. Finally, BMS-986158 showed antiviral activity in an HIV-1 acute infection model, possibly by arresting the cell cycle in infected cells. Thus, these results suggest that BMS-986158 is a potential candidate for AIDS/HIV-1 therapy.